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Molecular basis of MAPK-activated protein kinase 2:p38 assembly.

ABSTRACT: p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38alpha isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-A resolution crystal structure of the unphosphorylated complex between p38alpha and MK2. These protein kinases bind "head-to-head," present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366-Ala-390, which includes the bipartite nuclear localization signal, binds to the p38alpha-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38alpha binary assembly. The MK2 residues 345-365, containing the nuclear export signal, block access to the p38alpha active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38alpha and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein-protein interactions involving signal transduction proteins.

SUBMITTER: White A

PROVIDER: S-EPMC1851067 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Molecular basis of MAPK-activated protein kinase 2:p38 assembly.

White Andre A Pargellis Christopher A CA Studts Joey M JM Werneburg Brian G BG Farmer Bennett T BT

Proceedings of the National Academy of Sciences of the United States of America 20070329 15

p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38alpha isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-A resolution crystal structure of the unphosphorylated complex between p38alpha and MK2. These protein kinases bind "head-to-head," present their respective active sites on approximately t ...[more]

PMID: 17395714

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Project description:AimsSome asthma patients remain symptomatic despite using high doses of inhaled corticosteroids (ICS). We used alveolar macrophages to identify individual patients with insensitivity to corticosteroids and to evaluate the anti-inflammatory effects of a p38 mitogen-activated protein kinase (MAPK) inhibitor combined with a corticosteroid on these cells.MethodsAlveolar macrophages from 27 asthma patients (classified according to the Global Initiative for Asthma (GINA) treatment stage. Six GINA1, 10 GINA2 and 11 GINA3/4) were stimulated with lipoploysaccharide (LPS) (1 ?g ml(-1)). The effects of dexamethasone (dex 1-1000 nm), the p38 MAPK inhibitor 1-(5-tert-butyl-2-p-tolyl-2Hpyrazol-3-yl)-3(4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl)urea (BIRB-796 1-1000 nm) and both drugs combined at all concentrations on supernatant TNF?, IL-6 and CXCL-8 concentrations were analyzed by ELISA. Dose-sparing and efficacy enhancing effects of combination treatment were determined.ResultsDexamethasone reduced LPS-induced TNF?, IL-6 and CXCL-8 in all groups, but maximum inhibition was significantly reduced for GINA3/4 compared with GINA2 and GINA1 (P < 0.01). A subgroup of corticosteroid insensitive patients with a reduced effect of dexamethasone on cytokine secretion were identified. BIRB-796 in combination with dexamethasone significantly increased cytokine inhibition compared with either drug alone (P < 0.001) in all groups. This effect was greater in corticosteroid insensitive compared with sensitive patients. There were significant synergistic dose-sparing effects (P < 0.05) for the combination treatment on inhibition of TNF?, IL-6 and CXCL-8 in all groups. There was also significant efficacy enhancing benefits (P < 0.05) on TNF? and IL-6.Conclusionsp38 MAPK inhibitors synergistically enhance efficacy of corticosteroids in macrophages from asthma patients. This effect is greater in corticosteroid insensitive asthma patients, suggesting that this class of drug should be targeted to this patient phenotype.

Dataset Information

Molecular basis of MAPK-activated protein kinase 2:p38 assembly.

Publications

Molecular basis of MAPK-activated protein kinase 2:p38 assembly.

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